Overcoming Obstacles to Glioma Immunotherapy

Abstract

Glioma is a type of malignant tumor of the non-neuronal cells of the central nervous system, the glia. These tumors are the most common malignant tumors of the central nervous system. The most aggressive and most prevalent of these, glioblastoma multiforme (GBM) is a deadly disease with a grim prognosis, with median survival at diagnosis of less than a year and a half. Standard treatment with irradiation and the DNA alkylating drug temozolomide yields incremental improvement in survival over irradiation alone but better therapies remain needed. Immune therapies are an emerging class of therapies that have shown great promise in the treatment of hematopoietic malignancies and solid tumors. These therapies harness the capability of the immune system to target and kill large numbers of tumor cells specifically, and it is has been suggested that most or all durable responses to treatment of solid tumors involve generation of an anti-tumor immune response. Several anecdotal reports of dramatic responses in GBM patients after receiving cancer vaccines (a type of immune therapy) suggest that immune therapies for glioma could yield substantial increases in survival of patients with these tumors. However, the overall record of vaccines for the treatment of this disease has been marked by failure, and substantial barriers remain to the implementation of other types of immune therapies in glioma patients. Several mechanisms by which tumors in general, and brain tumors in particular, evade the activity of the immune system have been outlined. These include accumulation of immune suppressive cell types, tumor intrinsic changes that directly suppress the activity of infiltrating immune cells, and brain specific mechanisms of immune privilege. While these mechanisms are doubtless operative in many cases, accumulating evidence from clinical trials of adoptive transfer of T cells demonstrate that the accumulation of sufficient numbers of tumor-specific T lymphocytes at the tumor site can result in an overwhelming anti-tumor immune response and associated durable clinical responses. Therefore, my research over the past several years has focused on clinically relevant mechanisms in glioma patients that present obstacles to the development of a robust T cell mediated anti-tumor immune response. In this thesis, I outline experiments performed to understand and develop strategies for overcoming two obstacles to expanding large numbers of tumor specific cytolytic T lymphocytes in glioma patients: the anti-proliferative effect of the alkylating drug temozolomide on in vivo T cell expansion by cancer vaccination, and the differentiated phenotype of ex vivo expanded T cells for adoptive immunotherapy that is associated with diminished proliferative potential in vivo. A focus in these experiments is the targeting of tumors with T cells that are specific for antigenic determinants derived from tumor-specific mutations. Engineered T cell responses targeting individual patient-specific mutations may someday lead to significant improvements in the efficacy of immune therapy for glioma, and ultimately to improved outcomes for patients with these malignancies.